Retinal or optic nerve head damage, which can result in the loss of vision, is caused by trauma and various pathological events such as ischemia, hypoxia, or edema.
Retinal or optic nerve head ischemia or hypoxia occurs when the blood supply is significantly reduced to those tissues. Ischemia is a complex pathological episode involving numerous biochemical events. In recent years, the involvement of excitatory amino acids in ischemia-related neuronal and retinal damage has been implicated. (See, Choi, Excitatory cell death, Journal of Neurobiology, volume 23, pages 1261-1276 (1992); Tung et al., A quantitative analysis of the effects of excitatory neurotoxins on retinal ganglion cells in the chick, Visual Neuroscience, volume 4, pages 217-223 (1990); Sisk et al., Histologic changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate, Graefe's Archive for Clinical and Experimental Ophthalmology, volume 223, pages 250-258 (1985); Siliprandi et al., N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina, Visual Neuroscience, volume 8, pages 567-573 (1992); and David et al., Involvement of excitatory neurotransmitters in the damage produced in chick embryo retinas by anoxia and extracellular high potassium, Experimental Eye Research, volume 46, pages 657-662 (1988).)
During ischemia or hypoxia, excitatory amino acid levels are markedly elevated in neural tissue (Benveniste et al., Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis, Journal of Neurochemistry, volume 43, pages 1369-1374 (1984)), which may lead to excessive stimulation of post-synaptic excitatory amino acid receptors, and potentially result in cell injury. Release of excitatory amino acids has been reported to cause cytotoxicity due to increasing intracellular calcium levels, which in turn affect protein phosphorylation, proteolysis, lipolysis, and ultimately can result in cell death. (See, Choi, Glutamate neurotoxicity and diseases of the nervous system, Neuron, volume 1, pages 623-634 (1988); Siesjo, Calcium, excitotoxins, and brain damage, NIPS, volume 5, pages 120-125 (1990) and Olney et al., The role of specific ions in glutamate neurotoxicity, Neuroscience Letters, volume 65, pages 65-71 (1986).)
Antagonists against excitatory amino acid receptors have been shown to reduce neuronal and retinal damage in ischemic conditions. (See, Sheardown et al., 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia, Science, volume 247, pages 571-574 (1990); Scatton et al., Eliprodil Hydrochloride, Drugs of the Future, volume 19, pages 905-909 (1994); and Sucher et al., N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro, Journal of Neuroscience, volume 11, pages 966-971 (1991).)
Diabetic retinopathy is an ophthalmic disease leading to impaired vision and even total blindness. It has been reported that glutamate excitotoxicity has played a role in such vision loss. (See, Ambati, et al., Elevated GABA, Glutamate, and VEGF in the Vitreous of Humans With Proliferative Diabetic Retinopathy, Invest. Ophthalmol. Vis. Sci., volume 38, page S771 (1997), (elevated levels of glutamate in vitreous samples obtained from patients with proliferative diabetic retinopathy who underwent pars plana vitrectomy were reported with the suggestion that these levels of glutamate are potentially toxic to retinal ganglion cells.); Lieth, et al., Glial Glutamate to Glutamine Conversion is Impaired in Retinas of Diabetic Rats, Invest. Ophthalmol. Vis. Sci., volume 38, page S695 (1997), (glial glutamate to glutamine conversion was reported to be impaired in the retinas of diabetic rats.); and Hudson, et al., Short-Wavelength and White-on-White Automated Static Perimetry in Patients With Clinically Significant Diabetic Macular Oedema (DMO), Invest. Ophthalmol. Vis. Sci., volume 38, page S768 (1997), (deficits in retinal function related to ganglion cell function were reported in patients with diabetic macular edema).)
There are at least three ionotropic neuronal receptors associated with excitotoxicity. These receptors have been classified by the agonists that preferentially activate the receptor: N-methyl-D-aspartate (NMDA); kainate; and AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid). These neuronal receptors are differentially distributed to specific cells in the retina. (See, generally, Massey, S., Cell types using glutamate as a neurotransmitter in the vertebrate retina, N. N. Osborne and G. J. Chader (Eds.) Progress in Retinal Research, Chapter 9, Pergammon Press: Oxford, 399-425 (1990); and Miller et al., Excitatory amino acid receptors in the vertebrate retina, in Retinal Transmitters and Modulators: Models for the Brain, (W. W. Morgan, Ed.) CRC Press, Inc., Boca Raton, II:123-160 (1985).) The localization of such receptors may account for the pathologies associated with glaucoma or retinal ischemia. For example, death of the retinal ganglion cell has been correlated with the NMDA receptor. (See Sucher et al., N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in retinal ganglion cells in vitro, J. Neurosci., volume 11, issue 4, pages 966-971 (1991).)
The NMDA receptor is further comprised of several subunit proteins. These heteromeric assemblies contain NMDR1 subunits together with one or more of four NR2 subunits (NR2A, B, C and D) in a pentameric assembly of uncertain stoichiometry (Kutsuwada et al., Molecular diversity of the NMDA receptor channel. Nature, volume 358, pages 36-41 (1992)). The NR2B subunit of the NMDA receptor is a potential target by which some or all of the neuroprotective effects of certain compounds may be mediated (see, e.g., Fischer et al., RO-25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J. Pharmacol. Expt. Ther., volume 283, pages 1285-1292 (1997)).
Various ligands bind the NR2B subunit. For example, ifenprodil and its stereoisomers have been claimed to bind to the NR2B receptor subunit (Avenet et al., Antagonist properties of the stereoisomers of ifenprodil at NR1A/NR2A and NR1A/NR2B subtypes of the NMDA receptor expressed in xenopus oocytes. Eur. J. Pharmacology, volume 296, pages 209-213 (1996)). It is believed that selective blockade of the NR2B subunit may prevent the sequence of neurotoxic events following over activation of the NMDA receptor by elevated levels of glutamate.
NMDA receptor antagonists have been pursued in the art for neuroprotection. Given the numerous insults on a cell during ischemia and other trauma, however, the use of NMDA receptor antagonists alone may not provide the cytoprotective efficacy necessary to avoid neurodegeneration. There is a need, therefore, for compounds with broader inhibitory roles, i.e., compounds with dual pharmacophore efficacy, that may provide the added cytoprotective efficacy needed to prevent, reduce or ameliorate neuronal degradation.